Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-[2-[5-(1H-benzimidazole-2-thione)]ethyl]-4-arylpiperazines.

Docking of several 1-[2-[5-(1H-benzimidazole-2-thione)]ethyl]-4- and 1-benzyl-arylpiperazines to the D(2) dopamine receptor (DAR) was examined. The binding pocket of the D(2) DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trp182 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl, CF(3), and NO(2)) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D(2) DAR.

Electrostatic surface potential calculation on several new halogenated benzimidazole-like dopaminergic ligands.

We examined the effects of the electron density distribution (electrostatic surface potential; ESP) of several new benzimidazole-type ligands on their binding affinity for the D(1) and D(2) dopamine receptors (DAR). Receptors were prepared from synaptosomal membranes of bovine caudate nuclei. [(3)H]SCH 23390 and [(3)H]spiperone were used as specific radiolabels for the D(1) and D(2) receptors, respectively. The ESP of these compounds was calculated using Gaussian 98 W software. Calculations performed with known dopaminergic ligands showed that the electron density charge in the aromatic ring of these compounds favors a higher binding affinity for the D(2) DAR. This was confirmed by the synthesis of halogenated analogues of several known dopaminergic ligands. Halogenation resulted in an increase in the positive charge of the aromatic part of the molecule. None of the newly synthesized compounds was efficient in displacing [(3)H]SCH 23390 from the D1 DAR. The introduction of chlorine into the molecule led to a higher binding affinity for the D(2) DAR of the new ligands in comparison to both parent compounds and brominated ligands. This difference probably originates from the difference in the sizes of chlorine and bromine atoms, which could influence the interaction of a ligand with the receptor binding site. However, among the new ligands with bromine as a substituent, two compounds (8b and 10b) expressed a higher binding affinity and two of them (9b and 11b) a lower binding affinity for the D(2) DAR, when compared to unsubstituted parent compounds. These results indicate that the electrostatic surface potential of a ligand is an important factor in its interaction with the D(2) DAR and that this should be taken into account during design and synthesis of dopaminergic compounds.